Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice

Guoqing Sheng, Xingshun Xu, Yung Feng Lin, Chuan En Wang, Juan Rong, Dongmei Cheng, Junmin Peng, Xiaoyan Jiang, Shi Hua Li, Xiao Jiang Li

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72 Citations (Scopus)


Joubert syndrome is an autosomal recessive disorder characterized by congenital malformation of the cerebellum and brainstem, with abnormal decussation in the brain. Mutations in the Abelson helper integration site 1 gene, which encodes the protein AHI1, have been shown to cause Joubert syndrome. In this study, we found that mouse Ahi1 formed a stable complex with huntingtin-associated protein 1 (Hap1), which is critical for neonatal development and involved in intracellular trafficking. Hap1-knockout mice showed significantly reduced Ahi1 levels, defective cerebellar development, and abnormal axonal decussation. Suppression of Ahi1 also decreased the level of Hap1; and truncated Ahi1, which corresponds to the mutations in Joubert syndrome, inhibited neurite outgrowth in neuronal culture. Reducing Hap1 expression suppressed the level and internalization of TrkB, a neurotrophic factor receptor that mediates neurogenesis and neuronal differentiation, which led to decreased TrkB signaling. These findings provide insight into the pathogenesis of Joubert syndrome and demonstrate the critical role of the Ahi1-Hap1 complex in early brain development.

Original languageEnglish
Pages (from-to)2785-2795
Number of pages11
JournalJournal of Clinical Investigation
Issue number8
Publication statusPublished - Aug 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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